Urinary incontinence is particularly prevalent, debilitating, costly and complex in the frail elderly. Frail older adults are at risk for detrusor underactivity (DU), a condition present in nearly 2/3 of incontinent nursing home residents. DU influences the clinical presentation and may impede therapy of acute urinary retention, chronic urinary retention, benign prostatic hyperplasia and detrusor overactivity. Detrusor Hyperactivity with Impaired Contractility (DHIC) is especially common and challenging. Its clinical management remains unsatisfactory since anticholinergic antispasmodic medications may worsen retention, while current DU treatments are ineffective. Presence of detrusor muscle degeneration, fibrosis and axonal degeneration defines DU in human bladder biopsies. Our goals will be accomplished via 4 Specific Aims: AIM 1. Examine role of urinary retention in promoting bladder muscle loss, fibrosis and axonal degeneration, focusing on those pathways which may be shared with other risk factors, thus permitting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that an atypical cytokine called MIF (macrophage migration inhibitory factor) is involved in the pathways by which urinary retention promotes muscle loss, fibrosis and axonal degeneration following MIFs release from abundant urothelial stores. AIM 2. Examine role of estrogen depletion in bladder muscle loss, fibrosis and axonal degeneration, focusing on those pathways which may be shared with other risk factors, thus permiting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that MIF is also involved in the pathways by which ovariectomy promotes muscle loss, fibrosis and axonal degeneration. AIM 3. Examine the impact of aging on the ability of the bladder to respond to urinary retention or ovariectomy, focusing on those pathways which aging may share with the other risk factors, thus permitting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that aging enhances the bladder's vulnerability to develop muscle loss, fibrosis and axonal up AIM 4. Examine impact of aging on the ability of the urothelium to function as a regulatory interface between physical, inflammatory and endocrine stimuli involved in muscle loss, fibrosis and axonal degeneration. We propose that the urothelium represents a regulatory site where physical, inflammatory and endocrine stimuli interact in influencing the synthesis and release of MIF and other inflammatory mediators. We also propose that with aging, non-epithelial bladder tissues assume an unexpected importance as a major source of MIF, shifting the locus of control away from urothelial cells.